Necroptotic Signaling Orchestrates GBM Malignancy and Potentiates Temozolomide Response

Glioblastoma (GBM), a highly aggressive form of glioma, poses serious harm to patients due to its extremely poor prognosis and severe resistance to chemotherapeutic agents. Although programmed necrosis (necroptosis) has been implicated in GBM progression, its precise function and biological significance in GBM remain incompletely defined. Here, we show that elevated expression of key necroptotic machinery proteins, including RIPK1 and MLKL, is positively associated with disease progression and predicts poor prognosis in glioma patients. Functionally, RIPK1 promotes glioblastoma cell proliferation, migration, and invasion. Genetic ablation of RIPK1 induces cell-cycle arrest and suppresses tumor growth in subcutaneous xenograft models, whereas pharmacological inhibition of RIPK1 with necrostatin-1 fails to restrict GBM cell expansion, suggesting that RIPK1 exerts oncogenic effects independent of its canonical necroptotic role. Notably, dual apoptosis- and necroptosis-inducing agents, ZZW115 and citronellol, synergize with temozolomide (TMZ)—the first-line chemotherapy for GBM—to enhance glioma cell death and increase tumor clearance in an orthotopic mouse glioma model. Collectively, these findings identify RIPK1 as a critical driver of glioma malignancy and underscore the therapeutic potential of activating necroptosis to augment TMZ efficacy, providing a framework for novel prognostic and treatment strategies in glioma.